tbuckley/cabot-search huggingface dataset:
Impact of age on functional decline following radical nephrectomy: Analysis of the International Marker Consortium for Renal Cancer (INMARC).
Authors: Mimi Nguyen, Arman Walia, Ava Saidian, Luke Wang, Kevin Hakimi, Margaret Meagher, Clara Cerrato, Aastha Shah, Franklin Liu, Sohail Dhanji, Dattatraya H Patil, Yasuhisa Fujii, Ithaar H Derweesh
Journal: Journal of Clinical Oncology (2023)

664 Background: Radical nephrectomy (RN) is a mainstay of management of localized renal cancer &gt;4 cm. RN is associated with renal functional decline, however impact of age on functional decline is unclear. We investigated impact of age on post RN function, focusing on decline to moderate and severe chronic kidney disease (CKD). Methods: This was a retrospective analysis of patients who underwent RN. Patients were stratified by age (&lt;50, 50-70 and &gt;70 years). Primary outcome was development of denovo CKD-S 3b [estimated glomerular filtration rate (eGFR) &lt;45 mL/min/1.73m2)]. Secondary outcomes included denovo CKD-S 3a (eGFR&lt;60) and denovo CKD-S 4 (eGFR&lt;30). Multivariable logistic regression analysis (MVA) was utilized to identify risk factors for renal functional decline. Linear regression was utilized to identify risk factors for increasing DeGFR. Kaplan-Meier analysis (KMA) was utilized to evaluate functional outcomes for different age groups Results: We analyzed 2436 patients (&lt;50 years, n=513; 50-70 years, n=1344; &gt;70, n=579; median follow-up 31.9 months). On MVA, increasing age was an independent risk factor for CKD-S 3a (HR=3.4-9.4, p&lt;0.001), CKD-S 3b (HR=3.4-7.7, p&lt;0.001), and denovo CKD-S 4 (HR=1.96, p=0.027). On linear-regression analysis, increasing age was significantly correlated with increased delta eGFR (β=-0.212, p&lt;0.001). KMA Comparing &lt;50, 50-70 and &gt;70 demonstrated age-associated declines in 5-year freedom from denovo CKD-S 3a (73.9%; 50-70 53.7%; and &gt;70 37.06%, respectively, p&lt;0.001), denovo CKD-S 3b (92.7%; 71.8%; and 55.5%, p&lt;0.001) and denovo CKD-S 4 (93.7%; 89.8%; and &gt;70 81.2%, p&lt;0.001). Conclusions: Increasing age is a risk factor for progressive and clinically significant renal functional decline after RN. Prioritization for nephron-sparing management may be considered when indicated and oncologically safe and feasible in elderly patients to reduce potential risk of sequelae of functional decline. [Table: see text]
Systematic literature review and testing of HER2 status in urothelial carcinoma (UC).
Authors: Vadim S Koshkin, Christine Boyiddle, Naomi Schwartz, Judy Yu, Kristina S. Yu, Ashley Kang, Lisa Bloudek, Qijun Fang, Johanna M. Schafer, Amanda F. Baker, Farzaneh H. Sayedian, Emilie Scherrer
Journal: Journal of Clinical Oncology (2023)

556 Background: Recent clinical trials suggest an emerging role for HER2-targeted therapy in locally advanced and metastatic UC (LA/mUC). The prevalence of HER2 expression and gene amplification (encoded by ERBB2) in LA/mUC has not been well defined, as testing for HER2 expression in LA/mUC is not part of current routine practice and is not standardized. We report (1) findings of a systematic literature review (SLR) of HER2 status in LA/mUC and (2) preliminary results of an ongoing evaluation of HER2 status in UC assaying HER2 protein expression by immunohistochemistry (IHC) and gene amplification by in situ hybridization (ISH). Methods: (1) The SLR used databases PubMed and EMBASE to identify English-language studies of LA/mUC HER2 status published Jan2000 – Oct2021. We used the following definitions: HER2-positive (HER2+) was defined as IHC 3+, or IHC 2+ with HER2 gene amplification (Amp+). HER2-low was defined as IHC 2+/Amp–, or as IHC 1+. HER2-zero was defined as IHC 0. Weighted averages were calculated to estimate population prevalence. (2) Commercially sourced, formalin-fixed paraffin-embedded surgical resections of primary UC were evaluated by trained readers for HER2 protein expression using the VENTANA HER2/neu (4B5) Rabbit Monoclonal Primary Antibody IHC assay and for HER2 gene amplification using the VENTANA HER2 Dual ISH DNA Probe Cocktail that detects both ERBB2 and its residing chromosome, chromosome 17 (Chr17), using a two-color chromogenic stain. HER2 IHC staining was scored based on an established scoring algorithm for gastric cancer. HER2 gene amplification was defined by a HER2/Chr17 ratio ≥2.0. Results: (1) Of 744 records screened for the SLR, 45 studies reported HER2 status, including 10,602 patients (pts) with LA/mUC. A variety of assays and scoring guidelines were used. In the 4 studies (862 pts) reporting data applicable to our predefined criteria for HER2 status, the percentage of HER2+ ranged from 6.7% to 37.5% (weighted average, 13.1%; 95% CI, 7.3%–18.8%). (2) Of 252 UC samples evaluated, 38 were HER2+ (15.1%; 95% CI, 11.2%–20.0%), 74 were HER2-low (29.4%; 95% CI, 24.1%–35.3%), and 140 were HER2-zero (55.5%; 95% CI: 49.4%–61.6%; Table). The HER2 gene was amplified in 31 (12.3%), among them 24 (77.4%) at stage III or IV muscle-invasive UC (MIUC). Conclusions: The SLR revealed wide variability of HER2 status in LA/mUC, highlighting a lack of standardized methods for assessing and defining HER2 status. In our large study using standardized laboratory methods, 44% of UC samples were HER2+ or HER2-low, and HER2 status distribution was consistent with that reported for pts with LA/mUC. Results suggest a potentially important role for HER2-targeted therapy for UC. [Table: see text]
Real-world combination therapy patterns in patients receiving leuprolide or relugolix for androgen deprivation therapy in 2021 (The REAL-ADT COMBO Study): Analysis from a US EMR database.
Authors: Rana R. McKay, Raj Gandhi, Eric Yang, Janis Pruett, Esmond Nwokeji, Mark Fallick
Journal: Journal of Clinical Oncology (2023)

74 Background: Relugolix, an oral gonadotropin releasing hormone (GnRH) receptor antagonist, was FDA approved for the treatment of adults with advanced prostate cancer (PC) in December 2020 and became commercially available in January 2021. Data from a subgroup of patients from the Phase 3 HERO study showed patients combining relugolix with enzalutamide or docetaxel had similar efficacy and safety as other cohorts in the study. However, due to limited data, some guidelines do not recommend relugolix in combination with other therapies. We evaluated real world utilization of leuprolide and relugolix in combination with other PC medications. Methods: An observational retrospective analysis was conducted using Electronic Medical Record (EMR) data. PPS Analytics data from 89 urology practices with patients represented across all 50 states in the US were analyzed. Patients with at least one record of androgen deprivation therapy (ADT) in 2021 were included. Patients whose date of ADT initiation could not be determined were excluded from this analysis. This analysis focused on the occurrence of patients with ADT as well as in combination with other PC medications. Data are reported for all patients treated with leuprolide or relugolix and stratified by new and continuing ADT use. Combination PC medications were reported for these two ADT groups. Results: In 2021, 51,735 patients were treated with ADT; 45,599 (88.1%) were treated with leuprolide and 3,096 (6.0%) patients had at least 1 prescription for relugolix. Combination PC medications (ComboPCRx) were proportionately higher in relugolix patients than in leuprolide patients (698 [22.5%] vs 8,897 [19.5%] respectively; p &lt; 0.0001). ComboPCRx in users new to ADT was more frequent for relugolix users (342/2,169 [15.8%]) than for leuprolide users (1934/17,737 [10.9%]). In both groups, novel anti-androgens were the most frequent type of ComboPCRx. Conclusions: In this real-world EMR analysis, relugolix use in combination with other PC medication was frequently observed, for both new to ADT and continuing ADT patients. The percentage of combination therapy with PC medications was higher for relugolix users than it was for leuprolide users. These results provide insight into the real-world use of relugolix in combination with other PC medications. Further analyses are needed to make informed treatment decisions. [Table: see text]
HDR brachytherapy and radiotherapy as salvage treatment for macroscopic recurrence in the prostate bed after radical prostatectomy.
Authors: Benjamin Guix, Marco Panichi, Ivan Garcia, Emma Gonzalez, Dina Najjari, Ines Guix, Fernando Costa, Josep Maria Sole, Teresa Guix, Luis Quinzaños
Journal: Journal of Clinical Oncology (2023)

370 Background: To present early and late toxicity, biochemical, local, regional and distant control and survival in a prospective series of 75 patients with macroscopic local recurrence in the prostate bed after radical prostatectomy treated by salvage HDR brachytherapy. Methods: Between 12/1999 and 12/2020, 75 patients (pts) with exclusive macroscopic recurrence in the prostate bed after radical prostatectomy without nodal or distant metastases, were included in the study. Pts were prospectively treated by 46 Gy IMRT radiotherapy to the surgical bed followed by 16 Gy HDR brachytherapy in 2 implants of 8Gy each, one week apart and hormone therapy for 36 months. Rectal limitant dose was 85% and for urethra 115% of the prescribed dose. Toxicity was recorded according to the EORTC/RTOG criteria. Special attention to PSA levels, biochemical, local, nodal and distant metastases control and survival, as well as to quality of life was taken. Results: All pts completed treatment. No pts experienced grade 3 or higher rectal or urinary toxicity. odos los pacientes completaron el tratamiento. 2 pts presented G1 rectal toxicity (ocasional rectorragia) and 1 pts G2 rectitis (persistent rectorragia), that ceased with topic treatment (cortisone ointment) 1 Pts had G1 urethral toxicity (dysuria), that spontaneously disappeared qat few months no requiring any medical intervention. No patient developed stenosis, necrosis or urethral fistula during follow-up. With a median follow-up of 102 months, 13 pts had failure of the disease: 6 biochemical-only, 2 local recurrence, 2 pelvic recurrence, 1 paraaortic recurrence and 2 distant metastases. 2 patients died by the disease and 1 patient died by other cause (age related). Conclusions: IMRT plus HDR brachytherapy was a safe treatment without any early or late significant side-effect. Combined treatment by IMRT and HDR plus androgen deprivation was extraordinary effective in the control or macroscopic local recurrences in the prostatectomy bed after radical prostatectomy. Further studies are warranted.
Gene signatures for predicting the response to immune checkpoint inhibitor by integrating bulk and single-cell sequence data in patients with bladder cancer.
Authors: Hyun Chang, Yongho Kim, Jeong Won Lee, Jin-Woo Jung, Byung Il Yoon
Journal: Journal of Clinical Oncology (2023)

535 Background: Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in bladder cancer (BC) therapy, only a limited fraction of patients benefit from it. Thus, we aim to establish gene signature (iGS) and develop a model that predicts the response of ICI for the patients with BC. Methods: We collected bulk RNA expression data from BC cohort (GSE176307) receiving ICI and single-cell sequencing data from patients with BC (GSE135337). Single-sample gene set enrichment (ssGSEA) analysis was used to develop predictive iGS. Clinical benefit of ICI was defined as a complete or partial response or stable disease at week 24. The gene ontology (GO) and pathway enrichment analysis were established through DAVID database. Logistic regression model was constructed with iGS and clinical factors. The final model was validated by the K-fold cross validation technique. Results: We integrated bulk RNA expression data and single-cell sequencing data, and identified subset of cells (N= 157) that were associated with the overall survival (OS) of patients receiving ICI. These cells were compared with all other cells, and 85 up-regulated differentially expressed genes (DEGs) were identified. DEGs were mainly enriched in 'antigen processing and presentation of exogenous peptide antigen via MHC class II', 'peptide antigen assembly with MHC class II protein complex' and 'immune response' in the biological process enrichment analysis. High iGS score, that was derived from ssGSEA, was significantly associated with longer OS in multivariate Cox regression analysis (Hazard ratio: 0.40, P = 0.02) Final prediction model for clinical benefit included iGS score [odds ratio (OR) = 3.89], tumor mutation burden (OR = 9.8) and age (OR = 0.93) with accuracy of 0.80 and an area under the receiver operator characteristic curve (AUROC) of 0.77. Conclusions: We showed the potential of iGS from bulk and single cell RNA sequencing for predicting clinical benefit of ICI in BC.
Enfortumab vedotin (EV) outcomes with and without immediate prior immune checkpoint inhibitor (ICI) in patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Vadim S Koshkin, Nicholas Henderson, Deepak Kilari, Tanya Jindal, Omar Alhalabi, Dory Freeman, Arnab Basu, Pedro C. Barata, Mehmet Asim Bilen, Yousef Zakharia, Hamid Emamekhoo, Sumit Shah, Matthew I. Milowsky, Nancy B. Davis, Shilpa Gupta, Christopher J. Hoimes, Petros Grivas, Joaquim Bellmunt, Matthew T Campbell, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2023)

514 Background: EV is FDA-approved in pts with aUC and ≥1 prior therapy line. Data from EV-103 trial indicate robust response to first-line EV/pembrolizumab, suggesting potentially at least additive treatment effect with EV/ICI combination. Given the long half-life of ICIs, pts who start EV treatment immediately after ICI may potentially derive benefit from that therapy sequence. We hypothesized that the last systemic therapy prior to EV would impact outcomes, as pts treated with ICI immediately prior to EV would have superior outcomes relative to pts treated with chemotherapy (chemo). Methods: UNITE is a retrospective study of pts treated with EV at 16 US sites. Pt characteristics and outcomes were abstracted from EMR review at each site. Observed response was determined by investigators for evaluable pts with scans following ≥1 EV dose. Pts treated with EV monotherapy were divided into two groups based on whether they received chemo or ICI as the line of therapy immediately prior to EV, regardless of other therapy received. Chi-squared test was used to assess differences in pt characteristics and ORR while log-rank tests were used for OS and PFS measured from EV start. Results: Among 325 pts treated with EV monotherapy, 247 had chemo or ICI as immediate prior treatment, with 186 pts receiving ICI (Group A) and 61 pts receiving platinum-based chemo (Group B). In 247-pt cohort, ORR to EV was 52% and mPFS and mOS were 6 and 13 mos. Group B pts were younger, had more bone mets and higher Bellmunt risk factors, but were otherwise similar to Group A (Table). Most pts had both prior chemo and ICI in both group A (58%) and group B (84%). Group A pts had shorter time from last treatment (median 1.2 vs 3.2 mo, p&lt;0.01), lower ORR to immediate prior treatment (16% vs 37%, p&lt;0.01) and fewer prior therapy lines (mean 1.9 vs 2.6, p&lt;0.01). Group A had superior ORR (58% vs 37%, p=0.02), mPFS (6.9 vs 4.8 mo, p=0.02) and mOS (15.2 vs 8.8 mo, p=0.01) from EV start vs Group B. Conclusions: Pts with aUC treated with EV had superior outcomes if they received ICI instead of chemo as immediate prior treatment, suggesting the hypothesis that this may represent an optimal therapy sequence or combination. These data need external validation as limitations include retrospective design, lack of randomization, and selection and confounding biases. [Table: see text]
Oncological outcomes with wide resection in robot-assisted radical prostatectomy as primary treatment for very high-risk prostate cancer.
Authors: Noriyoshi Miura, Katsuyoshi Hashine, Ryuta Watanabe, Terutaka Noda, Kenichi Nishimura, Tetsuya Fukumoto, Yuki Miyauchi, Tadahiko Kikugawa, Takatoshi Tacho, Takahiro Yanagaki, Akihiro Oka, Hajime Takeda, Yuichi Watanabe, Iku Ninomiya, Akitomi Shirato, Takashi Saika
Journal: Journal of Clinical Oncology (2023)

357 Background: Patients with very high-risk prostate cancer (VHRPCa) have earlier biochemical recurrences (BCRs) and higher mortality rates. It remains unclear whether extended robot-assisted radical prostatectomy (eRARP) with intended wide resection can improve the outcomes of VHRPCa patients. We aimed to compare the oncological outcomes of eRARP versus standard RALP (sRARP) for primary treatment of VHRPCa. Methods: We retrospectively evaluated 168 patients classified by the National Comprehensive Cancer Network (NCCN) as very high-risk who were treated with RARP without neoadjuvant/adjuvant therapy between September 2011 and December 2020. eRARP was performed using the extra-fascial approach as reported by Gandaglia G et al. (Eur Urol. 71:249-256, 2017). We performed 1:1 propensity score matching to account for potential differences between eRARP and sRARP. Kaplan-Meier analysis and Cox regression models were used to test the effect of eRARP on the biochemical progression-free survival (bPFS). This observational study was approved by the Institutional Review Board. Results: There were 93 patients in the eRARP group and 75 in the sRARP group. The eRARP group had a worse clinical stage than the sRARP group ( p&lt; 0.001). Age, pretreatment prostate specific antigen (PSA), and pretreatment Gleason score were similar in the two groups. All patients in the eRARP group underwent pelvic lymph node dissection, compared with 89% in the sRARP group. The propensity-adjusted 3-year biochemical recurrence-free survival rates was 31.4% in the sRARP group and 67.4% in the eRARP group(p=0.001), respectively. The adjusted Cox regression analysis showed that the eRARP group had a significantly longer bPFS than the sRARP group (hazard ratio 0.415, p=0.0047). Conclusions: In patients with VHRPCa, eRARP was associated with a reduce risk of biochemical recurrence. These results suggest that eRARP may improve oncological outcomes in VHRPCa.
A phase II study of nivolumab with ipilimumab and cabozantinib in patients with untreated renal cell carcinoma brain metastases.
Authors: Jianbo Wang, Matthew T Campbell, Amishi Yogesh Shah, Sangeeta Goswami, Pavlos Msaouel, Omar Alhalabi, Andrew Warren Hahn, Craig A. Kovitz, Bagi RP Jana, John C. Araujo, Jianjun Gao, Amado J. Zurita, Eric Jonasch, Paul Gettys Corn, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2023)

TPS745 Background: A SEER analysis from 2010 to 2013 demonstrated that the incidence of brain metastases(mets) at the diagnosis of renal cell carcinoma(RCC) is 1.51%, and around 12% of patients(pts) with advanced RCC (aRCC) also had mets to the brain. Brain mets confer a poor prognosis. Local management strategies for brain mets from RCC include surgical resection, stereotactic radiosurgery and whole brain radiation therapy. Although systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is a potent small molecule inhibitor of multiple tyrosine kinases that was approved by FDA for pts with aRCC alone or in combination with nivolumab. Cabozantinib has demonstrated activity in patients with intracranial tumors. A phase III trial (COSMIC-313) recently evaluated cabozantinib in combination with nivolumab and ipilimumab compared to nivolumab plus ipilimumab and demonstrated significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. The combination was found to be safe as frontline systemic treatment. The role of this combination in patients with aRCC with brain mets remains undefined. As such, we propose a study to assess the safety and efficacy of cabozantinib in combination with nivolumab/ipilimumab in RCC pts with untreated brain mets. We believe the results from this trial could provide additional treatment options for pts with RCC brain mets who are typically excluded from clinical trials. Methods: This is a phase II study to assess the safety and efficacy of the combination of nivolumab with ipilimumab and cabozantinib in pts with untreated brain mets from RCC until disease progression or intolerable toxicities or patient withdrawal. Planned accrual is 40 pts. Pts will be treated with nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily. Then pts will be treated with nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until progression or intolerable toxicities or patient’s withdrawal. A lead-in group of 6 pts will be closely monitored for dose limiting toxicities(DLT). If stopping criteria (&gt;3 patients develop DLTs) is met, then treatment will be switched to nivolumab plus cabozantinib omitting ipilimumab. The primary objective is intracranial progression free survival(PFS). Secondary objectives include intracranial safety, objective response rate (intracranial + extracranial) by modified RECIST v1.1 and RECIST v1.1, extracranial PFS and overall survival. This phase II trial is currently enrolling pts. Clinical trial information: NCT05048212 .
Phase 2 open label study of durvalumab with neoadjuvant chemotherapy in variant histology bladder cancer.
Authors: Ali Raza Khaki, Alice C. Fan, Sumit Shah, Divya Ahuja Parikh, Joanne Chien, Kaidi Moore, Shann Mika Ruiz, Denise Haas, Laith Fakhoury, Noël Del Toro, Paige Baker, Aidan O'Brien, Sandy Srinivas
Journal: Journal of Clinical Oncology (2023)

524 Background: The immune-responsive nature of bladder cancer has made it an active area of interest for novel applications of immune checkpoint inhibitors (ICIs), with multiple ICI agents approved in the metastatic setting and ongoing perioperative trials. Variant histology urothelial carcinoma is a rare, heterogenous, and aggressive disease category associated with poor prognosis and response to standard therapies. This investigator-initiated phase 2 trial explored the addition of durvalumab to neoadjuvant chemotherapy (NAC) in the setting of variant histology MIBC. Methods: Patients with cT2-T4a, N0-N1, M0 histologically-confirmed bladder cancer of variant histology who were candidates for platinum-based NAC and radical cystectomy were eligible for the study. Enrolled patients received durvalumab with each cycle of investigator’s choice of platinum NAC (ddMVAC, cisplatin/gemcitabine, or carboplatin/gemcitabine). The primary objective was to determine the safety and tolerability of each study treatment as assessed by the total number of adverse events of grade 3 or higher, judged by the investigator as probably or definitely related to durvalumab. Secondary objective was to determine the percent of subjects post neoadjuvant chemo immunotherapy who achieve tumor stage of pT2N0M0 or better at cystectomy. Target accrual was 24 patients. Results: Six patients were enrolled (the study closed early due to low accrual). Median age was 72 years, 17% were women, 67% were white, 33% were Asian. 50% received ddMVAC and 50% received carboplatin/gemcitabine. All patients completed the planned cycles of NAC and durvalumab (4 cycles) and 5/6 proceeded to radical cystectomy (one patient declined cystectomy). Three patients experienced a Grade 3 AE that was assessed by the investigator to be related to treatment (table). One patient with sarcomatoid and glandular histology had pathological complete response and one patient with papillary and 10% squamous had pT2N0 at cystectomy. Conclusions: The addition of durvalumab to platinum NAC for patients with variant-histology muscle invasive bladder cancer demonstrates a reasonable safety and tolerability profile. Further investigation into this combination is warranted in larger scale trials. Clinical trial information: NCT03912818 . [Table: see text]